Common Modes of Action of γ-Butyrolactones and Pentylenetetrazol on the GABAA Receptor-Ionophore Complex

Article abstract of DOI:10.1016/0922-4106(94)90010-8

The effects of pentylenetetrazol and bicyclic γ-butyrolactones of similar stereostructures were studied on the convulsant and benzodiazepine binding sites and chloride ionophore activity of the γ-aminobutyric acid (GABA_A) receptor-complex. Bicyclic γ-butyrolactones displayed millimolar IC50 values and low stereoselectivities on [35S]t-butylbicyclophosphorothionate (TBPS) binding to the convulsant sites in synaptosomal membranes of rat forebrains. Ring saturation of bicyclic γ-butyrolactones decreased their IC50 values by one order of magnitude. The IC50 values of saturated bicyclic γ-butyrolactones and pentylenetetrazol were increased by GABA versus its antagonist R 5135 (3α-hydroxy-16-imino-5β,17-aza-androstan-11-one). A bicyclic γ-butyrolactone and pentylenetetrazol accelarated the dissociation of [35S]TBPS, displaced [3H]flumezenil binding in two phases and blocked the muscimol-elicited chloride currents in patch-clamped cortical neurones in culture in a similar manner. These similar effects on binding and ionophore function suppert their common modes of action on the GABA_A receptor-ionophore complex.